Gas permeable sealing member for drug container and methods of assembly

ABSTRACT

Drug delivery devices, sealing members for containers housed within such drug delivery devices, and related methods of assembly are disclosed. The drug delivery device may include a housing, a container disposed in the housing and having an interior volume, a drug disposed in the interior volume, and a septum. The container may have an opening formed in an end surface and which communicates with the interior volume. The septum may include a proximal end inserted through the opening into the interior volume of the container. Additionally, the septum may include a distal end having a flange disposed outwardly of the proximal end and contacting the end surface of the container. At least an end portion of the flange may be made of a material that is permeable to a gaseous sterilizing agent.

CROSS-REFERENCE TO RELATED APPLICATION

This is the United States National Phase of PCT/US2018/041567, filedJul. 11, 2018, which claims the priority benefit of U.S. ProvisionalPatent Application No. 62/535,777, filed Jul. 21, 2017, the entirecontents of each of which are hereby incorporated herein by reference.

FIELD OF DISCLOSURE

The present disclosure generally relates to drug containers and, moreparticularly, to the assembly and sterilization of such containerswithin an injection.

BACKGROUND

Many drug containers or vials include an opening covered by a septum,which is also sometimes referred to as a stopper. The septum seals thedrug within the container and usually is pierceable by a needle or othersharpened member to provide fluid communication with the drug.Conventional septa typically are constructed of a material with a verylow gas and/or moisture permeability rate, to prevent the ingress ofcontaminants and leakage of the drug compositions. A risk ofcontamination nevertheless exits along the interface where the septumcontacts the container.

Some drug containers are filled and closed with a septum under sterileor aseptic conditions, and thereafter stored within medical gradepackaging until use by a patient or healthcare provider. Under suchcircumstances the risk of contamination of the interface between theseptum and the container is low. In other scenarios, the drug containermay be exposed to non-sterile or non-aseptic conditions during thefilling procedure, thereby resulting in a risk of contamination at theinterface between the septum and the container after the fillingprocedure. One such scenario is when a manufacturer installs apre-filled drug container in a drug delivery device, such as a wearableinjector or a pen-type injector, with the objective of creating apre-filled and pre-loaded drug delivery device. Contamination can occur,for example, during the transport of the pre-filled drug containerbetween the filling facility and the installation facility and/or withinareas of the installation facility which are not operated under sterileor aseptic conditions. To address this contamination risk, oftentimesthe manufacturer will subject the drug delivery device to asterilization treatment near the end of the assembly process.

At this stage, however, the available sterilization treatments may belimited. This is because certain sterilization treatments can havedeleterious effects on the drug within the container and/or the materialused to construct the container. Radiation sterilization (e.g., gammaray sterilization or electron beam sterilization) may cause oxidation ofthe drug and/or discoloration of the container glass. Though gaseoussterilization treatments such as ethylene oxide (EtO) and steamtreatments may not cause damage to the drug or container material, inmany cases they are not effective at killing bacteria or sporesinoculated at the interface between a conventional septum and thecontainer. Conventional septa have very low gas permeability rates andtherefore will block the gaseous sterilization agent from reaching theinterface between the septum and the container. It has been found thateven extended ethylene oxide treatments (e.g., up to 30 hours) are noteffective at sterilizing the interface between a conventional septum andthe container. Furthermore, extended ethylene oxide treatments posesignificant manufacturing challenges since they require long aerationcycles (e.g., 30-60 days) to extract residual ethylene oxide from thecontainer and other components of the drug delivery device.

The present disclosure sets forth septa, container assemblies, drugdelivery devices, and related methods of assembly embodying advantageousalternatives to existing versions of such devices and methods, and thatmay address one or more of the challenges or needs mentioned herein, aswell as provide other benefits and advantages.

SUMMARY

One aspect of the present disclosure provides a drug delivery deviceincluding a housing, a container, a drug, and a septum. The containermay be disposed in the housing and have an interior volume and an endsurface. An opening may be formed in the end surface and communicatewith the interior volume. The drug may be disposed in the interiorvolume of the container. The septum may include a proximal end and adistal end. The proximal end of the septum may be inserted through theopening into the interior volume of the container. The distal end of theseptum may include a flange disposed outwardly of the proximal end andcontacting the end surface of the container. At least an end portion ofthe flange may be made of a first material, and the first material maybe permeable to a gaseous sterilizing agent. Furthermore, at least aportion of the distal end of the septum may be made of a secondmaterial.

Another aspect of the present disclosure provides a method of assemblinga drug delivery device, the method including: (a) providing a containerassembly including a container having an interior volume and an endsurface, an opening being formed in the end surface and communicatingwith the interior volume, and a septum including a proximal end and adistal end, the proximal end being inserted through the opening into theinterior volume of the container, the distal end including a flangedisposed outwardly of the proximal end and contacting the end surface ofthe container, at least an end portion of the flange being made of afirst material, where the first material is permeable to a gaseoussterilizing agent; (b) sterilizing the container assembly with a gaseoussterilizing agent such that the gaseous sterilizing agent diffusesthrough the first material to sterilize the end surface of thecontainer; (c) filling the interior volume of the container with a drug;and (d) installing the container assembly in the drug delivery device.

Yet another aspect of the present disclosure provides container assemblyincluding a container and a septum. The container may have a containerhaving an interior volume and an end surface. An opening may be formedin the end surface and communicate with the interior volume. The septummay include a proximal end and a distal end. The proximal end of theseptum may be insertable through the opening into the interior volume ofthe container. The distal end of the assembly may include a flangedisposed outwardly of the proximal end. At least an end portion of theflange may be made of a first material, and the first material maybepermeable to a gaseous sterilizing agent. At least a portion of thedistal end of the septum may be made of a second material.

An additional aspect of the present disclosure provides a containerassembly including a container, a septum, and a ring-shaped sealingmember. The container may have an interior volume and an end surface. Anopening may be formed in the end surface and communicate with theinterior volume. The septum may include a proximal end and a distal end.The proximal end of the septum may be insertable through the openinginto the interior volume of the container. The distal end of the septummay include a flange disposed outwardly of the proximal end. Thering-shaped sealing member may be positioned between the flange and theend surface of the container. The ring-shaped sealing member may be madeof a first material, and the first material maybe permeable to a gaseoussterilizing agent.

Another aspect of the present disclosure provides a septum for a drugcontainer. The septum may include a longitudinal axis, a proximal endinsertable into the drug container, and a distal end including a flangedisposed radially outwardly of the proximal end. The flange may includean outer peripheral surface and a proximally facing surface. At least anend portion of the flange may be made of a first material. The firstmaterial may be permeable to a gaseous sterilizing agent such that thegaseous sterilizing agent is permitted to diffuse through the firstmaterial between the outer peripheral surface of the flange and theproximally facing surface of the flange. At least a portion of thedistal end of the septum may be made of a second material.

Yet another aspect of the present disclosure provides a drug deliverydevice including a housing, a container, a drug, and a septum. Thecontainer may be disposed in the housing and have an interior volume andan end surface. An opening may be formed in the end surface andcommunicate with the interior volume. The drug may be disposed in theinterior volume of the container. The septum may include a proximal endand a distal end. The proximal end of the septum may be inserted throughthe opening into the interior volume of the container. The distal end ofthe septum may include a flange disposed outwardly of the proximal endand contacting the end surface of the container. Furthermore, anentirety of the septum may be made of a material that is permeable to agaseous sterilizing agent.

BRIEF DESCRIPTION OF THE DRAWINGS

It is believed that the disclosure will be more fully understood fromthe following description taken in conjunction with the accompanyingdrawings. Some of the drawings may have been simplified by the omissionof selected elements for the purpose of more clearly showing otherelements. Such omissions of elements in some drawings are notnecessarily indicative of the presence or absence of particular elementsin any of the exemplary embodiments, except as may be explicitlydelineated in the corresponding written description. Also, none of thedrawings is necessarily to scale.

FIG. 1 illustrates a schematic cross-sectional view of an embodiment ofa drug delivery device in accordance with principles of the presentdisclosure.

FIG. 2A depicts an exploded view of a container assembly depicted inFIG. 1 , with the container and stopper being illustrated incross-section.

FIG. 2B illustrates an assembled view of the container assemblyillustrated in FIG. 2A, with the container, the stopper, and thefastener being shown in cross-section.

FIG. 3A is a top perspective view of a septum depicted in FIGS. 1-2B.

FIG. 3B is a bottom perspective view of the septum depicted in FIG. 3A.

FIG. 4 is a cross-sectional view of an embodiment of a septumconstructed in accordance with principles of the present disclosure.

FIG. 5 is a cross-sectional view of another embodiment of a septumconstructed in accordance with principles of the present disclosure.

FIG. 6 is a cross-sectional view of yet another embodiment of a septumconstructed in accordance with principles of the present disclosure.

FIG. 7 is a cross-sectional view of still another embodiment of a septumconstructed in accordance with principles of the present disclosure.

FIG. 8 is a partial cross-sectional view of the embodiment of the septumof FIG. 5 , coated with a resin film.

FIG. 9A depicts an exploded view of another embodiment of a containerassembly, with a container, stopper, and ring-shaped sealing memberbeing shown in cross-section.

FIG. 9B illustrates an assembled view of the container assemblyillustrated in FIG. 9A, with the container, the stopper, the ring-shapedsealing member, and the fastener being shown in cross-section.

FIG. 10 is a top perspective view of the ring-shaped sealing memberdepicted in FIGS. 9A and 9B.

DETAILED DESCRIPTION

The present disclosure generally concerns protecting a drug stored in acontainer (e.g., a vial or ampule) from microbes and other contaminants.Sealing close an opening of such containers is often accomplished with aseptum, or what is referred to by some as a stopper. The septum mayinclude a proximal or bottom end that is inserted through the openinginto the container, and an enlarged distal or top end that abuts againstan end surface or rim of the container. The engagement of the enlargeddistal end of the septum and the end surface of the container mayinhibit the ingress of contaminants. In addition to providing acontaminant barrier, the presently disclosed septa advantageouslyfacilitate the sterilization of an interface between the septum and thecontainer during manufacturing. This aspect of the presently disclosedsepta is facilitated by constructing the septum, at least partially, ofa material that is permeable to gaseous sterilizing agent(s) such asethylene oxide (EtO) and/or steam, for example. This permeability mayallow a gaseous sterilizing agent to diffuse through the septum andsterilize the interface between the septum and the container. Otherportions of the septum may be constructed of a different material whichis less permeable, or even non-permeable, to the gaseous sterilizingagent, thereby resulting in a composite septum made of at least twodifferent materials. Also, as described below, the embodiments of theseptum according to the present disclosure advantageously permit a drugcontainer, which may or may not be pre-filled, to be installed orassembled in a drug delivery device under non-sterile or non-asepticconditions, and then later subjected to a gaseous sterilizationtreatment without damaging the drug stored in the container. Furtherdisclosed is a sealing member such as a gasket which is separate fromthe septum and positioned between the septum and the end surface of thecontainer. The sealing member may be constructed of a material that ispermeable to a gaseous sterilizing agent to provide a diffusion pathwayfor a gaseous sterilizing agent to eliminate or reduce contaminantsexisting at the end surface of the container.

Each of the foregoing components and methods of assembling a drugdelivery device including these components will now be described in moredetail.

Before describing various embodiments of a septum constructed inaccordance with principles of the present disclosure, a general overviewof a drug delivery device is provided with reference to FIG. 1 , inwhich the below-described septum embodiments can be implemented.

FIG. 1 illustrates an embodiment of a drug delivery device 10 which maybe operated to subcutaneously or transdermally deliver a drug to apatient. In the illustrated embodiment, the drug delivery device 10 isconfigured as a wearable drug delivery device, such as an on-bodyinjector or an ambulatory infusion pump, which is releasably attached tothe patient's tissue 11 (e.g., the patient's skin). In other embodiments(not illustrated), the drug delivery device 10 may be configured as apen-type injector, such as an autoinjector or injection pen, which istemporarily held against the patient's tissue 11 over the course of theinjection. The drug delivery device 10 may be configured toautomatically deliver a fixed or a patient/operator-settable dose of thedrug over a controlled or selected period of time. Furthermore, the drugdelivery device 10 may be intended for self-administration by thepatient, or may be operated by a formally trained healthcareprofessional or other caregiver to administer the injection.

Generally, the drug delivery device 10 may include an insertionmechanism 12, a container 14, a fluid pathway assembly 22, a drivemechanism 24, and a controller 26, each of which may be disposed withinan interior space of a main housing 29. An actuator 28 (e.g., auser-depressible button, touchscreen, microphone, etc.) may protrudethrough or otherwise be disposed at an exterior surface of the housing29 and may be configured to initiate operation of the drug deliverydevice 10 by activating, via mechanical and/or electrical means (shownin dotted lines in FIG. 1 ), the insertion mechanism 12, the fluidpathway assembly 22, the drive mechanism 24, the controller 26, and/orother mechanisms and/or electronics. In embodiments where the actuator28 is a button that is depressed or otherwise physically moved by a useror patient, the actuator 28 may be configured to exert a motive forceneeded to activate the insertion mechanism 12, the fluid pathwayassembly 22, the drive assembly 24, the controller 26, and/or othermechanisms. In such embodiments, the actuator 28 may be physicallyconnected to, either directly or indirectly via a mechanical linkage,the insertion mechanism 12, the drive mechanism 24, the fluid pathwayassembly 22, and/or other mechanisms such that manually depressing orotherwise interacting with the actuator 28 supplies the motive forcenecessary to activate the insertion mechanism 12, the drive mechanism24, the fluid pathway assembly 22, and/or other mechanisms. For example,in some embodiments, manually depressing the actuator 28 may cause thefluid pathway assembly 22 to move towards the stationary container 14,or cause the container 14 to move towards the stationary fluid pathwayassembly 22, and thereby cause a container access needle to penetratethrough a seal member into a reservoir or interior volume of thecontainer 14. Additionally or alternatively, the actuator 28 may operateas an input device that transmits an electrical and/or mechanical signalto the controller 26, which in turn may execute programmableinstructions to control operation of the insertion mechanism 12, thedrive mechanism 24, the fluid pathway assembly 22, and/or othermechanisms. In such embodiments, the controller 26 may include aprocessor (e.g., a microprocessor) and a non-transitory memory forstoring the programmable instructions to be executed by the processor.Furthermore, in such embodiments, the drug delivery device 10 mayinclude an internal actuator (e.g., an electric motor, a pneumatic orhydraulic pump, and/or a source of pressurized gas or liquid) which isseparate from the actuator 28 and which, in response to an electricalcontrol signal received from the controller 26, exerts the motive forceneeded to activate the insertion mechanism 12, the drive mechanism 24,the fluid pathway assembly 22, and/or other mechanisms.

Still referring to FIG. 1 , the housing 29 may include a bottom wall 25configured to be releasably attached (e.g., adhered with an adhesive) tothe patient's tissue 11, and a top wall 27 including one or more visualindicators 42 (e.g., lights, graphical displays, etc.) and/or a window35 for viewing the container 14 and the drug 32 contained therein. Theone or more visual indicators 42 may be used to communicate informationto the user about the operational state of the drug delivery device 10and/or the condition of the drug 32. An opening 31 may be formed in thebottom wall 25, and optionally a pierceable sterile barrier 33 mayextend across the opening 31 to seal the interior of the housing 29prior to use. In some embodiments, the pierceable sterile barrier 33 maybe omitted, and instead a removable sealing member (not illustrated) maycover and seal close the opening 31 prior to use.

More particularly with respect to the window 35, this element may beconstructed of a transparent or semi-transparent material and generallyaligned with the container 14, so as to allow a patient or user of thedrug delivery device 10 to inspect the drug 32 within the container 14and/or confirm dose completion. Suitable materials for constructing thewindow 35 include, but are not limited to, glass and plastic. Since thewindow 35 is located on the exterior of the drug delivery device 10, itmay expose the drug 32 to ambient light such as sunlight. Some drugs maybe sensitive to certain wavelengths of light and undergo undesirablemolecular changes when exposed to light. For example, some drugs may besensitive to wavelengths of light in the ultraviolet (UV) range, thevisible range, and/or the infrared range. To protect drugs that areprimarily sensitive to light in the UV range and/or the infrared range,a dark tint may be added to the window 35 and/or the window 35 may bedimensioned to cover a relatively small surface area of the housing 29.For drugs that are primarily sensitive to light in the visible range, itmay not be necessary to add a dark tint to the window 35 and/or shrinkthe size of the window 35. Instead, the window 35 may be constructedwith a polarized filter. In some embodiments, the polarized filter maybe a film or other coating that is applied to the window 35. In otherembodiments, the polarized filter may be integrated directly into thematerial of window 35. The polarized filter may allow for viewing andinspection of the drug 32 within the container 14, while filtering outup to and including approximately (e.g., ±10%) 50% of light in thevisible range. In some embodiments, the portion of visible lightfiltered out by the window 35 may fall in a range between approximately(e.g., ±10%) 0-50%, or 10-50%, or 20-50%, or 25-50%, or 0-40%, or 0-30%,or 0-25%, depending on the photosensitivity of the drug 32 and/or thetypical eye strength of the patient population of the drug 32, amongother considerations. Adding the polarized filter to the window 35 inlieu adding a dark tint to the window 35 and/or shrinking the size ofthe window 35 advantageously protects the drug 35 from light in thevisible range without substantially compromising the ability of thepatient or user of the drug delivery device 10 to inspect the drug 32prior to and/or during the injection.

After the bottom wall 25 of the housing 29 is attached to the patient'stissue 13, the insertion mechanism 12 may be activated to move adelivery member from a retracted position within the housing 29 to adeployed position extending outside of the housing 29. In the presentembodiment, this involves the insertion mechanism 12 inserting a trocar21 and a hollow cannula 23 surrounding the trocar 21 through thepierceable sterile barrier 33 and into the patient's tissue 11, asillustrated in FIG. 1 . Immediately or shortly thereafter, the insertionmechanism 12 may automatically retract the trocar 21, leaving the distalopen end of the cannula 23 inside the patient for subcutaneous deliveryof the drug 32. The trocar 21 may be solid and have a sharpened end forpiercing the patient's skin 11. Furthermore, the trocar 21 may be madeof a material that is more rigid than the cannula 23. In someembodiments, the trocar 21 may be made of metal, whereas the cannula 23may be made of plastic or another polymer. The relative flexibility ofthe cannula 23 may allow it to be disposed subcutaneously within thepatient's tissue 11 for a period of a time without causing pain orsignificant discomfort to the patient. In other embodiments (notillustrated), the trocar 21 and cannula 23 may be omitted, and insteadthe insertion mechanism 12 may insert only a rigid, hollow needle intothe patient for subcutaneous delivery of the drug 32.

In some embodiments, the insertion mechanism 12 may include one or moresprings (e.g., coil springs, torsion springs, etc.) initially retainedin an energized state, and which are released upon depression of theactuator 28 in order to insert the trocar 21 and cannula 23, or hollowneedle, into the patient. Furthermore, retraction of the trocar 21 maybe achieved by the automatic release of another spring after the trocar21 and cannula 23 have been inserted into the patient. Other powersources for insertion and/or retraction are possible, including, forexample, an electric motor, a hydraulic or pneumatic pump, or a canisterthat releases a pressurized gas or pressurized liquid to provideactuation energy.

With continued reference to FIG. 1 , the container 14, which in somecontexts may be referred to as a primary container, may include a wall38 defining an interior volume 30 or reservoir that contains the drug32. In some embodiments, the interior volume 30 may be pre-filled withthe drug 32 by a drug manufacturer prior to installation of thecontainer 14 in the drug delivery device 10. In some embodiments, thecontainer 14 may be rigidly connected to the housing 29 such that thecontainer 14 cannot move relative to the housing; whereas, in otherembodiments, the container 14 may be slidably connected to the housing29 such that the container 14 can move relative to the housing 29 duringoperation of the drug delivery device 10. The container 14 may have anelongate, barrel-like or cylindrical shape extending along alongitudinal axis A. In embodiments where the drug delivery device 10 isconfigured as an on-body injector, the longitudinal axis A of thecontainer 14 may be perpendicular or substantially perpendicular, orotherwise non-parallel, to a direction in which the insertion mechanism12 inserts a delivery member such as the cannula 23 into the patient.This configuration may allow the on-body injector to have a generallyplanar, low profile shape that can be worn by the patient withoutimpeding the patient's movement. Initially, a stopper 34 or other pistonmember may be positioned in the interior volume 30 at a proximal end 36of the container 14. The stopper 34 may sealingly and slidably engage aninner surface 43 of the wall 38 of the container 14, and may be movablerelative to the wall 38 of the container 14.

The volume of the drug 32 contained in the container 14 prior todelivery may be: any volume in a range between approximately (e.g.,±10%) 0.5-20 mL, or any volume in a range between approximately (e.g.,±10%) 0.5-10 mL, or any volume in a range between approximately (e.g.,±10%) 1-10 mL, or any volume in a range between approximately (e.g.,±10%) 1-8 mL, or any volume in a range between approximately (e.g.,±10%) 1-5 mL, or any volume in a range between approximately (e.g.,±10%) 1-3.5 mL, or any volume in a range between approximately (e.g.,±10%) 1-3 mL, or any volume in a range between approximately (e.g.,±10%) 1-2.5 mL, or any volume in a range between approximately (e.g.,±10%) 1-2 mL, or any volume equal to or less than approximately (e.g.,±10%) 4 mL, or any volume equal to or less than approximately (e.g.,±10%) 3.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 3 mL, or any volume equal to or less than approximately (e.g.,±10%) 2.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 2 mL, or any volume equal to or less than approximately (e.g.,±10%) 1.5 mL, or any volume equal to or less than approximately (e.g.,±10%) 1 mL. The interior volume 30 of the container 14 may be completelyor partially filled with the drug 32. The drug 32 may be one or more ofthe drugs described below, such as, for example, a granulocytecolony-stimulating factor (G-CSF), a PCSK9 (Proprotein ConvertaseSubtilisin/Kexin Type 9) specific antibody, a sclerostin antibody, or acalcitonin gene-related peptide (CGRP) antibody.

During operation of the drug delivery device 10, the drive mechanism 24may push the stopper 34 along the longitudinal axis A from the proximalend 36 of the container 14 to the distal end 37 of the container 14 inorder to expel the drug 32 from the container 14. In some embodiments,the drive mechanism 24 may include one or more springs (e.g., coilsprings, torsion springs, etc.) initially retained in an energizedstate, and which are released upon depression of the actuator 28.Following their release, the spring(s) may expand and move the stopper34 through the interior volume 30 along the longitudinal axis A from theproximal end 36 of the container 14 to the distal end 37 of thecontainer 14. In other embodiments, the drive mechanism 24 may includean electric motor (not illustrated) which rotates a gear mechanism,including for example one or more sprocket gears, to cause axial motionof the stopper 34 through the interior volume 30. In still furtherembodiments, the drive mechanism 24 may include both an electric motorand spring(s), wherein the electric motor regulates expansion of thespring(s) via a tether or pulley system. In still further embodiments,the drive mechanism 24 may include a canister that releases apressurized gas or pressurized liquid to provide actuation energy.

At the distal end 37 of the container 14, an opening 45 (see FIG. 2A)may be formed in a distal end surface 72 (see FIG. 2A) of the wall 38.At least prior to operation of the drug delivery device 10, the opening45 may be covered and sealed closed by a septum 40 connected to thedistal end 37 of the container 14. Generally, the septum 40 may beconfigured to selectively permit access to the interior volume 30.During operation, the septum 40 may be physically altered to permitfluid communication with the drug 32 in the interior volume 30. Asdiscussed below, the septum 40 may be constructed of a flexible orelastically deformable material such as rubber, for example, which iscapable of being penetrated or pierced by a point or sharpened end 66 ofa container access needle 64 mounted on the fluid pathway assembly 22.In some embodiments, the septum 40 may be clamped or otherwise securedto the distal end surface 72 by a fastener 94 (see FIG. 2B) and/oradhered directly to the distal end surface 72.

Still referring to FIG. 1 , the fluid pathway assembly 22 may beconfigured to establish fluid communication between the container 14 andthe insertion mechanism 12 via a sterile fluid flow path duringoperation of the drug delivery device 10. Prior to use of the drugdelivery device 10, the fluid pathway assembly 22 may not be in fluidcommunication with the container 14. During setup of the drug deliverydevice 10, or during the initial stages of operation of the drugdelivery device 10 prior to drug delivery, the user may manually, or thedrug delivery device 10 may automatically, enable, connect, or open thenecessary connections to establish fluid communication between thecontainer 14 and the fluid pathway assembly 22. Subsequently, the drivemechanism 24 may move the stopper 34 in the distal direction to forcethe drug 32 stored in the container 14 through the sterile fluid flowpath of the fluid pathway assembly 22 and into the cannula 23 or needleof the insertion mechanism 12 for subcutaneous delivery to the patient.

In some embodiments, the fluid pathway assembly 22 may be rigidlyconnected to the housing 29 such that the fluid pathway assembly 22cannot move relative to the housing; whereas, in other embodiments, thefluid pathway assembly 22 may be slidably connected to the housing 29such that the fluid pathway assembly 22 can move relative to the housing29 during operation of the drug delivery device 10.

The fluid pathway assembly 22 may include a first end 44 having anopening, a second end 48 fluidly connected to the insertion mechanism12, and a fluid passage 50 extending between the first end 44 and thesecond end 48. The fluid passage 50 may be sterilized, and may bepartially or entirely made of a flexible tubing 52. Initially, there maybe slack in the flexible tubing 52 to allow the fluid pathway assembly22 to move relative to the housing 29 and/or to allow components of theinsertion mechanism 12 to which the fluid pathway assembly 22 isattached to move relative to the housing 29. In some embodiments, thefluid passage 50 may include a rigid fluid restrictor element (notillustrated) in addition to the flexible tubing 52. The fluid restrictorelement may have a smaller inner diameter than that of the flexibletubing 52 in order to regulate the flow rate of the drug 32 as it passesthrough the fluid pathway assembly 22. Furthermore, the fluid restrictorelement may be made of a more rigid material than the flexible tubing52. For example, the fluid restrictor element made be made of metal,whereas the flexible tubing 52 may be made of a polymeric material suchas plastic.

Prior to operation of the drug delivery device 10, the opening at thefirst end 44 of the fluid pathway assembly 22 may be covered andinitially sealed closed by a seal member 60 (e.g., a septum) which isconnected to the first end 44 of the fluid pathway assembly 22. In ageneral sense, the seal member 60 may be configured to control access tothe fluid passage 50. During operation of the device 10, in someembodiments the seal member 60 may be physically altered to permit fluidcommunication with the fluid passage 50. The seal member 60 may beaxially aligned with the septum 40 such that a proximal exterior endsurface of the seal member 60 faces a distal end surface of the septum40. In some embodiments, both the septum 40 and the seal member 60 maybe axially aligned along the longitudinal axis A of the container 14when installed in the drug delivery device 10. Additionally, in someembodiments the container access needle 64 may be axially aligned withthe longitudinal axis A of the container 14.

Still referring to FIG. 1 , the container access needle 64, which may berigid and hollow, may extend from the first end 44 of the fluid pathwayassembly 22. The first end 66 of the container access needle 64, whichmay be sharpened, may protrude from the first end 44 of the fluidpathway assembly 22; and a second end 68 of the container access needle64 may be in fluid communication with the fluid passage 50. The firstend 66 of the container access needle 64 may have an opening that isinitially covered and sealed by, or embedded within, the seal member 60.In some embodiments, the fluid pathway assembly 22 may include amounting member 51 or connection hub for rigidly connecting thecontainer access needle 64 to the remainder of the fluid pathwayassembly 22, so that the container access needle 64 cannot move relativeto the fluid pathway assembly 22, and so that, to the extent that thefluid pathway assembly 22 moves relative to the housing 29, the fluidpathway assembly 22 and the container access needle 64 move togetherjointly as a single unit relative to the housing 29. Furthermore, theseal member 60 may be mounted on the container access needle 64 so thatthe seal member 60 is connected to the first end 44 of the fluid pathwayassembly 22 by way of the container access needle 64. Furthermore, insuch embodiments, the seal member 60 may be constructed as a deformableseptum, or as a collapsible or rigid sleeve defining a sterile interiorchamber, enclosing the exposed first end 66 of the container accessneedle 64.

Furthermore, where appropriate, any of the above-describedsub-assemblies, mechanisms, components, features, functionalities,methods of manufacture, methods of use, and other aspects of the drugdelivery device 10 may be replaced with and/or combined with any of thesub-assemblies, mechanisms, components, features, functionalities,methods of manufacture, methods of use, and other aspects of the drugdelivery devices described in some or all of the following documents,each of which is hereby incorporated by reference in its entirety forall purposes: U.S. Pat. No. 9,061,097; U.S. Patent ApplicationPublication No. 2017/0124284; U.S. Patent Application Publication No.2017/0119969; U.S. Patent Application Publication No. 2017/0098058; U.S.Patent Application Publication No. 2017/0124285; U.S. Patent ApplicationPublication No. 2017/0103186; U.S. Provisional Patent Application No.62/460,501 entitled “INSERTION MECHANISM FOR DRUG DELIVERY DEVICE”; U.S.Provisional Patent Application No. 62/469,226 entitled “INSERTIONMECHANISM FOR DRUG DELIVERY DEVICE”; U.S. Provisional Patent ApplicationNo. 62/468,190 entitled “INSERTION MECHANISM AND METHOD OF INSERTING ANEEDLE OF A DRUG DELIVERY DEVICE”; U.S. Provisional Patent ApplicationNo. 62/460,559 entitled “DRUG DELIVERY DEVICE WITH STERILE FLUIDFLOWPATH AND RELATED METHOD OF ASSEMBLY”; U.S. Provisional PatentApplication No. 62/294,842 entitled “DRUG DELIVERY DEVICE, METHOD OFMANUFACTURE, AND METHOD OF USE”; U.S. Provisional Patent Application No.62/297,718 entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, ANDMETHOD OF USE”; U.S. Provisional Patent Application No. 62/320,438entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OFUSE”; International Patent Application No. PCT/US2017/017627 entitled“DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE”; andInternational Patent Application No. PCT/US2017/026524 entitled “DRUGDELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE”.

Turning to FIGS. 2A and 2B, illustrated is an enlarged view of thecontainer assembly of the drug delivery device 10. The containerassembly includes the container 14, the septum 40, and the stopper 34.The container 14 may have a generally cylindrical shape with an innerdiameter D1. At the distal end 37 of the container 14, the wall 38 mayprotrude radially outwardly to define a container flange 70. Thecontainer flange 70 may extend partially or entirely around acircumference of the distal end 37 of the container 14. The containerflange 70 may define a distal end surface 72 of the container 14, whichis perpendicular or otherwise non-parallel to the longitudinal axis A ofthe container 14 and generally faces in a distal direction. The opening45 may be formed in the distal end surface 72 and communicate with theinterior volume 30 of the container 14. In some embodiments, thecontainer flange 70 may be omitted such the distal end surface 72 doesnot project radially outwardly of a remainder of the container 14. Thewall 38 at the proximal end 36 of the container 14 may include aproximal end surface 78, which is perpendicular or otherwisenon-parallel to the longitudinal axis A of the container 14 andgenerally faces in a proximal direction. An opening 79 may be formed inthe proximal end surface 78 and communicate with the interior volume 30.The stopper 34 may inserted through the opening 79 into the interiorvolume 30 after the container 14 has been filled with the drug 32. Thecontainer 14 may be constructed of glass, plastic, or any other suitablyinert material which may not chemically interact with the drug 32.

Referring still to FIGS. 2A and 2B, the septum 40 may be centrallyaligned with the longitudinal axis A of the container 14 when the septum40 is inserted into the container 14 such that the septum 40 and thecontainer 14 share the same longitudinal axis A. The septum 40 may bedivided by an imaginary plane perpendicular to the longitudinal axis Ainto a proximal (or bottom) end 80 and a distal (or top) end 82. Theproximal end 80 and the distal end 82 may each possess a cylindricalshape and have outer diameters D2 and D3, respectively, as seen in FIG.2A. The distal end 82 may be enlarged relative to the proximal end 80,such that the outer diameter D3 (or other outer dimension) of the distalend 82 is larger than an outer diameter D2 (or other outer dimension) ofthe proximal end 80. A flange 84 of the septum 40 is defined by an outerperipheral (e.g., circumferential) portion of the distal end 82 of theseptum 40 that is disposed radially outwardly of the proximal end 80 ofthe septum 40. The flange 84 may have a length L1 parallel to thelongitudinal axis A and a width W1 perpendicular to the longitudinalaxis A.

The flange 84 of the septum 40 may include a proximal end portion 86 anda distal end portion 88, each of which has its boundary denoted bydashed lines in FIG. 2A. The proximal end portion 86 may have a lengthL2 parallel to the longitudinal axis A and a width W2 perpendicular tothe longitudinal axis A. Similarly, the distal end portion 88 maypossess a length L3 parallel to the longitudinal axis A and a width W3perpendicular to the longitudinal axis A. Each of the lengths L2 and L3may be less than the overall length L1 of the flange 84; whereas each ofthe widths W2 and W3 may be equal to the overall width W1 of the flange84 a. The proximal end portion 86 of the flange 84 may include: aproximal end surface 90 which is perpendicular or otherwise non-parallelto the longitudinal axis A and generally faces in the proximaldirection; and an outer peripheral (e.g., circumferential) surface 92which may be centered about and/or parallel to the longitudinal axis A.

Referring to FIG. 2B, when the septum 40 is attached to the container14, the proximal end 80 of the septum 40 may be inserted through theopening 45 into the interior volume 30 and the proximal end surface 90of the proximal end portion 86 of the flange 84 may directly contact andsealingly engage the distal end surface 72 of the container 14. In someembodiments, each of the proximal end surface 90 and the distal endsurface 72 may be planar such that they flushly engage each other. Inother embodiments, flush engagement may be achieved by configuring theproximal end surface 90 and the distal end surface 72 with matingcurvatures, such as one being convex and the other being concave.

Referring to FIG. 2B, a fastener 94 may be configured to hold the septum40 against the container 14. In some embodiments, the fastener 94 maytake the form of a crimp ring that is applied to the container 14 andseptum 40 with a crimping tool. As shown in FIG. 2B, the fastener 94 mayinclude radially inwardly extending flanges 96 and 98 that abut against,respectively, a proximally facing surface of the container flange 70 (orother exterior surface of the wall 38 of the container 14) and adistally facing end surface of the distal end 82 of the septum 40, inorder to clamp or press the proximal end surface 90 of the flange 84 ofthe septum 40 tightly against the distal end surface 72 of the container70. The clamping force provided by the fastener 94 may help ensure anair-tight and/or fluid-tight seal between the proximal end surface 90 ofthe flange 84 of the septum 40 and the distal end surface 72 of thecontainer 70. As described in more detail below, in some embodiments,the fastener 94 may be made of a material that is permeable to a gaseoussterilizing agent such as EtO and/or steam.

Still referring to FIG. 2B, the proximal end 80 of the septum 40 mayinclude one or more radially outwardly protruding annular ribs 100 forsealingly engaging the inner surface 43 of the wall 38 of the container14. The annular ribs 100 may provide a secondary barrier to prevent theingress contaminants that breach the seal between the proximal endsurface 90 of the flange 84 of the septum 40 and the distal end surface72 of the container 70. Here, the outer diameter D2 of the proximal end80 of the septum 40 may be equal to or less than inner diameter D1 ofthe container 14. In other embodiments, the annular ribs 100 may beomitted (see FIGS. 3A and 3B), and the outer diameter D2 of the proximalend 80 of the septum 40 may be slightly larger than the inner diameterD1 of the container 14 to provide a tight fit and seal. In still furtherembodiments, the annular ribs 100 may be omitted and the outer diameterD2 of the proximal end 80 of the septum 40 may be smaller than the innerdiameter D1 of the container 14, such that there is not a seal formedtherebetween.

Prior to placing the drug delivery device 10 in its final packaging orsealing close the interior space of the housing 29, it may beadvantageous to subject the fully or partially assembled drug deliverydevice 10 to a sterilization treatment in order to reduce or eliminatemicrobes or other contaminants, airborne or stationary, within or on thehousing 29. Such a sterilization treatment may be essential if any ofthe earlier steps of assembling the drug delivery device 10 occurred ina non-sterile or non-aseptic environment. Before its installation in thedrug delivery device 10, the container 14 may be filled and covered withthe septum 40 by a drug manufacturer in sterile or aseptic environment,where there is little risk of contamination. However, if the container14 is shipped to a manufacturer of the drug delivery device 10 and/orinstalled by the device manufacturer under non-sterile or non-asepticconditions, a risk exists that contaminants may breach the seal betweenthe septum 40 and the container 14 and become attached between theflange 84 of the septum 40 and the distal end surface 72 of thecontainer 14, or even potentially contaminate the drug 32. Thoughradiation sterilization (e.g., gamma ray sterilization or electron beamsterilization) might be able to sterilize contaminants at the interfacebetween the flange 84 of the septum 40 and the container 14, radiationsterilization after installation of the pre-filled container 14 in thedrug delivery device 10 may not be feasible due to the potential for thehigh energy sterilization beams to damage to the drug 32 in thecontainer 14. Gaseous sterilization treatments may not harm the drug 32,but may be unable to penetrate the seal between the flange 84 of theseptum 40 and the container 14 to sterilize the proximal end surface 90and/or the distal end surface 72.

To address this issue, the septum 40, the fastener 94, and/or othercomponents associated with the container 14 may be constructed,partially or entirely, of a material that is permeable to a gaseoussterilizing agent including, but not limited to, EtO and/or steam. Thismaterial may provide a diffusion pathway for molecules of the gaseoussterilizing agent to diffuse through at least the septum 40 andsterilize one or more surfaces, such as the proximal end surface 90and/or the distal end surface 72, that otherwise would be not feasibleto sterilize due to the inability of the gaseous sterilizing agent topenetrate the seal formed at the interface between the septum 40 and thecontainer 14.

FIGS. 4-7 illustrate four versions of the above-described septum 40,each having a different material composition but each having the samedimensional and geometric characteristics as those shown in FIGS. 1-3B.Each version of the septa 40 is appended with a respective one of thesuffixes: “a”, “b”, “c”, or “d”. Common to all versions of the septum 40a, 40 b, 40 c, and 40 d illustrated in FIGS. 4-7 is that at least theproximal end portion 86 of the flange 84, including its proximal endsurface 90 and outer peripheral surface 92, is made of a first materialthat is permeable to a gaseous sterilizing agent, including at least oneof EtO or steam. Accordingly, each of the septa 40 a-d has at least onediffusive pathway for the gaseous sterilizing agent extending betweenthe proximal end surface 90 and outer peripheral surface 92. Thus,during a sterilization procedure in which a partially or fully assembleddrug delivery device 10 is exposed to the gaseous sterilizing agent, thegaseous sterilizing agent can enter the septum 40 through at least theouter peripheral surface 92 and exit the septum 40 through at least theproximal end surface 90 to sterilize the interface between the septum 40and the container 40, including at least the proximal end surface 90 ofthe flange 84 and the distal end surface 72 of the container 14. In FIG.4 , for example, the diffusive pathway would extend from the peripheralsurface 92 a through to the proximal end surface 90 a. Other diffusivepathways through the septum 40 may also be possible, depending on theportion(s) of the septum 40 constructed of the first material that ispermeable to the gaseous sterilizing agent. The rate at which thegaseous sterilizing agent diffuses through each of the septa 40 a, 40 b,40 c, and 40 d may depend upon the proportion of the septum made of thefirst material. Also, although the one or more annular ribs 100 areomitted from FIGS. 4-7 , any of the embodiments of the septum 40 a, 40b, 40 c, and 40 d may include the one or more annular ribs 100.

Looking to FIG. 4 , illustrated is an embodiment of the septum 40 a inwhich only the proximal end portion 86 a of the flange 84 a may be madeof a first material that is permeable to a gaseous sterilizing agent,including at least one of EtO or steam. As such, only a ring-shapedportion of the septum 40 a defined by the proximal end portion 86 a ofthe flange 84 a may be made of the first material that is permeable tothe gaseous sterilizing agent. The remainder of the septum 40 a,including the distal end portion 88 of the flange 84 and the proximalend 80 a of the septum 40 a, may be made of a second material that isless permeable to the gaseous sterilizing agent than the first material.In some embodiments the second material may be substantially orcompletely impermeable to the gaseous sterilizing agent. Furthermore, insome embodiments of the septum 40 a, the gaseous sterilizing agent mayenter the septum 40 a only through the outer peripheral surface 92 a ofthe flange 84 a and exits the septum 40 a primarily or only through theproximal end surface 90 a of the flange 84. This may be useful inpreventing the gaseous sterilizing agent from entering the interiorvolume 30 of the container 14 and interacting with the drug 32.

FIG. 5 illustrates another embodiment of the septum 40 b, where thegaseous sterilizing agent may have additional ways to enter the septum40 b, including through the entire outer peripheral surface of thedistal end 82 b of the septum 40 b as well as the entire distal endsurface of the septum 40 b. This scheme may be achieved by constructingthe distal end 82 b of the septum 40 b entirely of the first materialthat is permeable to the gaseous sterilizing agent, including at leastone of EtO or steam. The proximal end 80 b of the septum 40 b may madeentirely of the second material which is less permeable to the gaseoussterilizing agent than the first material. In some embodiments thesecond material may be substantially or completely impermeable to thegaseous sterilizing agent. Similar to the septum 40 a, the gaseoussterilizing agent may exit the septum 40 b primarily or only through theproximal end surface 90 b of the flange 84 b. In some embodiments, thefirst material of the septum 40 b may be made of a polybutadiene rubber,and the second material of the septum 40 b may be made of a chlorobutylrubber.

Turning to FIG. 6 , depicted is yet another embodiment of the septum 40c. Here, a portion of the distal end 82 c of the septum 40 c that isarranged distally relative to the flange 80 c is made of theabove-mentioned second material. Stated another way, the portion of thedistal end 82 c of the septum 40 c that is arranged in the distaldirection relative to an imaginary plane that is perpendicular to thelongitudinal axis A and touches the distal end of the proximal endportion 86 c of the flange 84 c may be made of the second material. Theremainder of the distal end 82 c of the septum 40 c, including theproximal end portion 86 of the flange 84 and a portion of the distal end82 c of the septum 40 c located in the proximal direction relative tothe above-mentioned imaginary plane, may be made of the above-mentionedfirst material. Also, in the present embodiment of the septum 40 c, theproximal end 80 c of the septum 40 c may be made entirely of the firstmaterial. One benefit of the present embodiment of the septum 40 c isthat the gaseous sterilizing agent may be able to reach the innersurface 43 of the container 14 and sterilize any contaminants disposedthereon by diffusing through the proximal end 80 c of the septum 40 c.

FIG. 7 illustrates another embodiment of the septum 40 d, which is madeentirely of the above-mentioned first material. As such, both theproximal and distal ends 80 d and 82 d of the septum 40 d may beentirely of a material that is permeable to the gaseous sterilizingagent, including at least one of EtO or steam. This construction canhelp maximize the number diffusive pathways for the gaseous sterilizingagent. The gaseous sterilizing agent may be able to enter and exit theseptum 40 d through any exterior surface of the septum 40 d.Accordingly, it may be possible to sterilize the interface between theflange 84 d and the distal end surface 72 of the container 14, as wellas the interface between the proximal end 80 d of the septum 40 d andthe inner surface 43 of the container 14. Due to the relatively highpermeability of the septum 40 d, it may be beneficial to store the fullyassembled drug delivery device 10 inside a sealed and/or sterile spaceof a bag or other secondary packaging prior to use. This may prevent anygases and/or contaminants from diffusing through the septum 40 d in theperiod of time between assembly of the drug delivery device 10 and itsuse by a patient. In some embodiments, the secondary packaging may bemay be constructed of a multilayer material having gas barrierproperties. Moreover, any of the septa disclosed herein, including septa40 a, 40 b, 40 c, and 40 d may be installed in a drug delivery device 10that is subsequently placed within such secondary packaging, to provideadditional protection against contamination in the period of timebetween assembly of the drug delivery device 10 and use by a patient.

The following description of the first material and the second materialapplies to any one of the above-described septa 40 a, 40 b, 40 c, and 40d, and any other septum described herein. The composition of the firstmaterial may be chosen depending on any one of or any combination of thefollowing non-exclusive list of characteristics of a sterilizationprocedure (e.g., a terminal sterilization procedure) used to sterilizethe container 14 and/or other components of the drug delivery device 10:the composition of the gaseous sterilizing agent used in thesterilization procedure, the pressure of the gaseous sterilizing agentused in the sterilization procedure, the amount or volume of the gaseoussterilizing agent used in the sterilization procedure, the concentrationof the gaseous sterilizing agent used in the sterilization procedure,the length of time of the sterilization procedure, and the temperatureof the gaseous sterilizing agent used in the sterilization procedure. Insome embodiments, the first material may be permeable to any one of orany combination of the gaseous sterilizing agents chosen from thefollowing non-exclusive list of gaseous sterilizing agents: EtO, ozone,chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized watervapor). In some embodiments, the sterilization procedure utilizing steamas the gaseous sterilizing agent may be carried out within the interiorof inside an autoclave device. The first material may include any one ofor any combination of the following non-exclusive list of materials: apolymer, a rubber, and a polybutadiene rubber. The second material mayinclude any one of or any combination of the following non-exclusivelist of materials: a polymer, a rubber, a chlorobutyl rubber, and ahalobutyl rubber. In any of the above-described septa 40 a, 40 b, 40 c,and 40 d, and any other septum described herein, the first material maybe made of polybutadiene rubber, and the second material may be made ofchlorobutyl rubber.

In general, the second material is less permeable to the gaseoussterilizing agent than the first material, which includes the secondmaterial being substantially or completely impermeable to the gaseoussterilizing agent. In some embodiments, the rate of permeation of thefirst material may be at least 10 times, or at least 20 times, or atleast 30 times, or at least 40 times, or at least 50 times, or at least60 times, or at least 70 times, or at least 80 times, or at least 90times, or at least 100 times, greater than the rate of permeation of thesecond material.

Any one of the above-described septa 40 a, 40 b, 40 c, and 40 d, and anyother septum described herein, may be constructed as one-piececomponent, where the first and second materials are integrally formedwith each other, such as being injection molded with each other.Alternatively, any one of the above-described septa 40 a, 40 b, 40 c,and 40 d, and any other septum described herein, may be constructed as amulti-piece component, where the first material and the second materialare connected to each other via an adhesive, a fastener(s), and/or anyother suitable connecting element.

In embodiments where the fastener 94 is used hold the septum 40 againstthe container 14, the fastener ring 94 may act as a gas barrier thatinhibits the gaseous sterilizing agent from diffusing through thepermeable portion of the septum 40. Therefore, in some embodiments, oneor more openings 99 (see FIG. 2B) may be formed in the fastener ring 94to permit the gaseous sterilizing agent to pass through the fastener 94and into contact with the permeable portion of the septum 40. In someembodiments, the openings 99 may be arranged in a pattern and/or formedin an outer peripheral or circumferential surface of the fastener 94. Insome embodiments, the openings 99 may be located at the same axialposition as the outer peripheral surface 92 of the proximal end portion86 of the flange 84, as seen in FIG. 2B. In addition to the openings 99,or as an alternative to the openings 99, the fastener 94 may bepartially or entirely constructed of a material that is permeable to thegaseous sterilizing agent (e.g., EtO, ozone, chlorine dioxide, nitrogendioxide, and/or steam).

Turning to FIG. 8 , illustrated is an alternate version of the septum 40b, in which the exterior surface of the septum 40 b is partially coatedwith a chemically inert resin film 110. In some embodiments, the resinfilm 110 may be a fluoropolymer film. With reference to FIGS. 5 and 8 ,the resin film 110 may cover the entire exterior surface of the septum40 b, except for the proximal end surface 90 b and the outer peripheralsurface 92 b of the proximal end portion 86 b of the flange 84 b. Assuch, the resin film 110 may not inhibit the gaseous sterilizing agentfrom diffusing through the proximal end surface 90 b and the outerperipheral surface 92 b of the proximal end portion 86 b of the flange84 b. In some embodiments, the portion of the resin film 110 coveringthe proximal end 80 b and/or the distal end 82 b of the septum 40 bshown in FIG. 8 may be omitted. Also, any of the above-describedconfigurations of the resin film 110 may be applied to any of the septaembodiments disclosed herein, including septa 40 a, 40 c, and 40 d.

Each of the foregoing embodiments relies on the septum to provide adiffusive pathway for the gaseous sterilizing agent. However, thediffusive pathway may be achieved by other means as well. FIGS. 9A and9B illustrate an embodiment of the container assembly where thediffusive pathway is provided by a ring-shaped sealing member 300 orgasket which is separate from the septum 140. Elements of the containerassembly depicted in FIGS. 9A and 9B which are similar to those shown inFIGS. 2A and 2B are designated by the same reference numeral,incremented by 100. A description of many of these elements isabbreviated or even eliminated in the interest of brevity.

Referring to FIG. 9B, the ring-shaped sealing member 300, when assembledwith the other components of the container assembly, is positionedbetween the proximal end surface 190 of the flange 184 and the distalend surface 172 of the container 114. As seen in FIG. 10 , thering-shaped sealing member 300 may include a central opening 302extending between a proximal end surface 304 and a distal end surface306. The proximal end 180 of the septum 140 may be inserted through thecentral opening 302 as seen in FIG. 9B. The ring-shaped sealing member300 may also include an outer peripheral or circumferential surface 308that extends between the proximal end surface 304 and the distal endsurface 306.

During a sterilization procedure, the gaseous sterilizing agent mayenter the ring-shaped sealing member 300 through the outer peripheralsurface 308, diffuse through the material of the ring-shaped sealingmember 300, and exit the ring-shaped sealing member 300 through theproximal end surface 304. Accordingly, any microbes or othercontaminants attached at the interface between the ring-shaped sealingmember 300 and the container 114 may be reduced or eliminated. Thepermeability of the ring-shaped sealing member 300 may be achieved byconstructing the ring-shaped sealing member 300 of the first materialdescribed above. The foregoing description of the first material asincorporated into the septa 40 a-d applies equally to the first materialas incorporated into the ring-shaped sealing member 300.

With regard to the septum 140 which is used in combination with thering-shaped sealing member 300, it may be constructed partially orentirely of a material which is less permeable to the gaseoussterilizing agent than the material used to construct the ring-shapedsealing member 300. In some embodiments, the septum 140 may beconstructed partially or entirely of the second material describe above.In such embodiments, the foregoing description of the second material asincorporated into the septa 40 a-c is applicable to the second materialas incorporated into the septum 140. The ring-shaped sealing member 300advantageously provides a diffusive pathway for the gaseous sterilizingagent to sterilize the distal end surface 172 of the container 114should a conventional septum which is substantially or completelyimpermeable to the gaseous sterilizing agent be used to plug thecontainer 114. Furthermore, the ring-shaped sealing member 300 is notlimited for use with the septum 140; the ring-shaped sealing member 300may be used in combination with any of the septa disclosed herein,including any of septa 40 a-d.

Methods of assembling the drug delivery device 10 will now be described.Though the following description refers to the septum 40, it isapplicable to all version of the septum disclosed herein, including atleast septa 40 a, 40 b, 40,c, 40 d, and 140. Initially, the emptycontainer 14 and the septum 40 may be connected together and sterilized.This step may involve inserting the proximal end 80 of the septum 40through the opening 45 into the interior volume 30 of the container 14,and moving the proximal end surface 90 of the flange 84 into directcontact with the distal end surface 72 of the container 14. In someembodiments, connecting the container 14 and the septum 40 may involveclamping the two components together with the fastener 94 to provide anair-tight and/or fluid-tight seal between the proximal end surface 90 ofthe flange 84 and the distal end surface 72 of the container 14. Inembodiments where the ring-shaped sealing member 300 is included, theair-tight and/or fluid-tight seal may be created between the proximalend surface 304 of the ring-shaped sealing member 300 and the distal endsurface 172 of the container 114, as well as between the distal endsurface 306 of the ring-shaped sealing member 300 and the proximal endsurface 190 of the septum 140.

Next, the partially-assembled container 14 may be subjected to asterilization procedure or treatment. In some embodiments, thissterilization procedure may involve placing the partially-assembledcontainer 14 in a sealed vacuum chamber that is subsequently filled witha gaseous sterilizing agent. The gaseous sterilizing agent may be anyone of or any combination of the gaseous sterilizing agents chosen fromthe following non-exclusive list of gaseous sterilizing agents: EtO,ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurizedwater vapor). In embodiments where steam is utilized for sterilization,the chamber in which the sterilization procedure is carried out may bean autoclave. During this sterilization procedure, the septum 40, andthe ring-shaped sealing member 300 if it is included, may be exposed tothe gaseous sterilizing agent. The portions of the septum 40 and/or thering-shaped sealing member 300 constructed of the above-described firstmaterial may permit diffusion of the gaseous sterilizing agent such thatthe gaseous sterilizing agents diffuses through the septum 40 and/or thering-shaped sealing member 300 and sterilizes the interface between theseptum 40 or the ring-shaped sealing member 300 and the container 14, asdescribed above. The period of exposure time for the gaseous sterilizingagent may be relatively short due to the effectiveness with which thegaseous sterilizing agent can diffuse through the septum 40 and/or thering-shaped sealing member 300 and sterilize the interface at thecontainer 14. In some embodiments, the period of exposure time for thegaseous sterilizing agent may be: less than or equal to approximately(e.g., ±10%) 24 hours, or 18 hours, or 12 hours, or 8 hours, or 4 hours,or 2 hours, or 1 hour; or within a range between approximately (e.g.,±10%) 1-4 hours, or 4-8 hours, or 4-12 hours, or 4-18, or 8-12 hours, or8-18 hours, or 12-18 hours. The less time that the container 14 isexposed to the gaseous sterilizing agent, the less time that may neededfor aeration of the container 14 following the sterilization procedure.Accordingly, the presently disclosed septum and ring-shaped sealingmember may help streamline the manufacturing process of the container14. In alternative embodiments, this step of sterilizing thepartially-assembled container 14 may be omitted, or performed after thefilling procedure described in the following paragraph.

Next, the container 14 and the septum 40 may be aseptically transferredto a filling and capping environment. Here, the interior volume 30 ofthe container 14 may be filled with the drug 32, and then the proximalend 36 of the container 14 may be sealed closed with the stopper 34,which is slidably inserted through the opening 79. This filling andcapping environment may be operated as a sterile or aseptic assemblyenvironment to ensure that microbes and other contaminants are notcaptured within the interior volume 30. Subsequently, this drug-filled,pre-assembled container assembly may be packaged and shipped to afacility where the final assembly of the drug delivery device 10 is tooccur. Also, as a preliminary step, the fluid pathway assembly 22 may beconnected to the seal member 60 such that the seal member 60 seals closean open end of the fluid passage 50. The process of assembling the fluidpathway assembly 22 and the seal member 60 may be performed in a sterileor aseptic assembly environment to ensure that particulate contaminantsare not captured within the fluid passage 50. Alternatively oradditionally, the pre-assembled arrangement of the fluid pathwayassembly 22 and the seal member 60 may be subjected to high-energysterilization beams (e.g., gamma ray beams, x-ray beams, electron beams,etc.), ethylene oxide, or other known techniques to ensure theirsterility. This pre-assembled arrangement may then be packaged andshipped to a facility where the final assembly of the drug deliverydevice 10 is to occur.

Subsequently, at the final assembly facility for example, thedrug-filled, pre-assembled arrangement of the drug container 14, septum40, and stopper 34 and the pre-assembled arrangement of the fluidpathway assembly 22 and the seal member 60 may be installed within thehousing 29 of the drug delivery device 10. In some embodiments, thisinstallation process may involve: connecting the drug-filled,pre-assembled arrangement of the drug container 14, septum 40, andstopper 34 to a first housing portion (e.g., the bottom wall 25 of thehousing 29) or a second housing portion (e.g., the top wall 27 of thehousing 29) of the drug delivery device 10; and connecting thepre-assembled arrangement of the fluid pathway assembly 22 and the sealmember 60 to the first housing portion or the second housing portion ofthe drug delivery device 10. In some embodiments, the installation ofthe drug-filled, pre-assembled arrangement of the drug container 14,septum 40, and stopper 34 within the housing 29 and/or other steps ofthe assembly the drug delivery device 10 may be carried out in anon-sterile or non-aseptic environment. In other embodiments, theinstallation of the drug-filled, pre-assembled arrangement of the drugcontainer 14, septum 40, and stopper 34 within the housing 29 and someor all other steps of the assembly the drug delivery device 10 may becarried out in a sterile or aseptic environment.

After the drug-filled, pre-assembled arrangement of the drug container14, septum 40, and stopper 34 and/or the pre-assembled arrangement ofthe fluid pathway assembly 22 and the seal member 60 have been installedwithin the housing 29, this partially-assembled version of the drugdelivery device 10 may be subjected to a sterilization procedure ortreatment. In some embodiments, this sterilization procedure may involveplacing the partially-assembled version of the drug delivery device 10in a sealed vacuum chamber that is subsequently filled with a gaseoussterilizing agent. The gaseous sterilizing agent may be any one of orany combination of the gaseous sterilizing agents chosen from thefollowing non-exclusive list of gaseous sterilizing agents: EtO, ozone,chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized watervapor). In embodiments where steam is utilized for sterilization, thechamber in which the sterilization procedure is carried out may be anautoclave. During this sterilization procedure, the septum 40, and thering-shaped sealing member 300 if it is included, may be exposed to thegaseous sterilizing agent. The portions of the septum 40 and/or thering-shaped sealing member 300 constructed of the above-described firstmaterial may permit diffusion of the gaseous sterilizing agent such thatthe gaseous sterilizing agents diffuses through the septum 40 and/or thering-shaped sealing member 300 and sterilizes the interface between theseptum 40 or the ring-shaped sealing member 300 and the container 14, asdescribed above. The period of exposure time for the gaseous sterilizingagent may be relatively short due to the effectiveness with which thegaseous sterilizing agent can diffuse through the septum 40 and/or thering-shaped sealing member 300 and sterilize the interface at thecontainer 14. In some embodiments, the period of exposure time for thegaseous sterilizing agent may be: less than or equal to approximately(e.g., ±10%) 24 hours, or 18 hours, or 12 hours, or 8 hours, or 4 hours,or 2 hours, or 1 hour; or within a range between approximately (e.g.,±10%) 1-4 hours, or 4-8 hours, or 4-12 hours, or 4-18, or 8-12 hours, or8-18 hours, or 12-18 hours. The less time that the drug delivery device10 is exposed to the gaseous sterilizing agent, the less time that mayneeded for aeration of the drug delivery device 10 following thesterilization procedure. Accordingly, the presently disclosed septum andring-shaped sealing member may help streamline the manufacturing processof the drug delivery device 10.

After the sterilization procedure is complete, the first housing portionmay be connected to the second housing portion to enclose thedrug-filled, pre-assembled arrangement of the drug container 14, septum40, and stopper 34 and/or other components (e.g., the insertionmechanism 12, the fluid pathway assembly 22, the drive mechanism 24, thecontroller 26, etc.) within a sterilized interior space of the drugdelivery device 10. Accordingly, the enclosing step may result in apre-loaded and pre-filled drug delivery device 10. In some embodiments,the connection between the first and second housing portions may sealthe interior of the drug delivery 10 to prevent or inhibit the ingressof contaminants. Furthermore, in some embodiments, the first and secondhousing portions may be sealingly connected in the same environment orchamber in which the gaseous sterilization treatment was carried out.

It is noted that the foregoing method of assembly may be carried outwith any of the above-described embodiments of the septum 40, includingthe septa 40 a, 40 b, 40 c, 40 d, and 140 and/or the ring-shaped sealingmember 300.

Example

Described below are the results an experimental test comparing acomposite septum constructed in accordance with principles of thepresent disclosure relative to a conventional septum made entirely of agas impermeable material. Both the composite septum and the conventionalseptum had the proximal end surface of their flange inoculated withapproximately 10{circumflex over ( )}6 challenging microbes.Subsequently each septum was crimped against the distal end surface of adrug container. This process was repeated to create 30 samples utilizingthe composite septum and 30 samples utilizing the conventional septum.Next, the samples were subjected to a gaseous sterilization treatment inwhich EtO was employed as the gaseous sterilizing agent. After 18 hoursof EtO sterilization, no microbe growth was observed at the interfacebetween the composite septum and the drug container in all 30 samples.Some composite septum samples exhibited no microbe growth after only 8hours of EtO sterilization. By comparison, after 30 hours of EtOsterilization, only 15 of the 30 samples utilizing the conventionalseptum exhibited no microbe growth at the interface with the drugcontainer. Accordingly, the amount of time needed to sterilize theinterface between the presently disclosed composite septum and acontainer was empirically shown to be significantly less than thatneeded to sterilize the interface between a conventional septum and acontainer.

Drug Information

As mentioned above, the container may be filled with a drug. This drugmay be any one or combination of the drugs listed below, with the caveatthat the following list should neither be considered to be all inclusivenor limiting.

For example, the syringe may be filled with colony stimulating factors,such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agentsinclude, but are not limited to, Neupogen® (filgrastim) and Neulasta®(pegfilgrastim). In various other embodiments, the syringe may be usedwith various pharmaceutical products, such as an erythropoiesisstimulating agent (ESA), which may be in a liquid or a lyophilized form.An ESA is any molecule that stimulates erythropoiesis, such as Epogen®(epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta),Mircera® (methyoxy polyethylene glycol-epoetin beta), Hematide®,MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta),Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal,Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetintheta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetinzeta, epoetin theta, and epoetin delta, as well as the molecules orvariants or analogs thereof as disclosed in the following patents orpatent applications, each of which is herein incorporated by referencein its entirety: U.S. Pat. Nos. 4,703,008; 5,441,868; 5,547,933;5,618,698; 5,621,080; 5,756,349; 5,767,078; 5,773,569; 5,955,422;5,986,047; 6,583,272; 7,084,245; and 7,271,689; and PCT Publication Nos.WO 91/05867; WO 95/05465; WO 96/40772; WO 00/24893; WO 01/81405; and WO2007/136752.

An ESA can be an erythropoiesis stimulating protein. As used herein,“erythropoiesis stimulating protein” means any protein that directly orindirectly causes activation of the erythropoietin receptor, forexample, by binding to and causing dimerization of the receptor.Erythropoiesis stimulating proteins include erythropoietin and variants,analogs, or derivatives thereof that bind to and activate erythropoietinreceptor; antibodies that bind to erythropoietin receptor and activatethe receptor; or peptides that bind to and activate erythropoietinreceptor. Erythropoiesis stimulating proteins include, but are notlimited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega,epoetin iota, epoetin zeta, and analogs thereof, pegylatederythropoietin, carbamylated erythropoietin, mimetic peptides (includingEMP1/hematide), and mimetic antibodies. Exemplary erythropoiesisstimulating proteins include erythropoietin, darbepoetin, erythropoietinagonist variants, and peptides or antibodies that bind and activateerythropoietin receptor (and include compounds reported in U.S.Publication Nos. 2003/0215444 and 2006/0040858, the disclosures of eachof which is incorporated herein by reference in its entirety) as well aserythropoietin molecules or variants or analogs thereof as disclosed inthe following patents or patent applications, which are each hereinincorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008;5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078;5,773,569; 5,955,422; 5,830,851; 5,856,298; 5,986,047; 6,030,086;6,310,078; 6,391,633; 6,583,272; 6,586,398; 6,900,292; 6,750,369;7,030,226; 7,084,245; and 7,217,689; U.S. Publication Nos. 2002/0155998;2003/0077753; 2003/0082749; 2003/0143202; 2004/0009902; 2004/0071694;2004/0091961; 2004/0143857; 2004/0157293; 2004/0175379; 2004/0175824;2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914; 2005/0026834;2005/0096461; 2005/0107297; 2005/0107591; 2005/0124045; 2005/0124564;2005/0137329; 2005/0142642; 2005/0143292; 2005/0153879; 2005/0158822;2005/0158832; 2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;2005/0202538; 2005/0227289; 2005/0244409; 2006/0088906; and2006/0111279; and PCT Publication Nos. WO 91/05867; WO 95/05465; WO99/66054; WO 00/24893; WO 01/81405; WO 00/61637; WO 01/36489; WO02/014356; WO 02/19963; WO 02/20034; WO 02/49673; WO 02/085940; WO03/029291; WO 2003/055526; WO 2003/084477; WO 2003/094858; WO2004/002417; WO 2004/002424; WO 2004/009627; WO 2004/024761; WO2004/033651; WO 2004/035603; WO 2004/043382; WO 2004/101600; WO2004/101606; WO 2004/101611; WO 2004/106373; WO 2004/018667; WO2005/001025; WO 2005/001136; WO 2005/021579; WO 2005/025606; WO2005/032460; WO 2005/051327; WO 2005/063808; WO 2005/063809; WO2005/070451; WO 2005/081687; WO 2005/084711; WO 2005/103076; WO2005/100403; WO 2005/092369; WO 2006/50959; WO 2006/02646; and WO2006/29094.

Examples of other pharmaceutical products for use with the device mayinclude, but are not limited to, antibodies such as Vectibix®(panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); otherbiological agents such as Enbrel® (etanercept, TNF-receptor/Fc fusionprotein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF,hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such asSensipar® (cinacalcet). The device may also be used with a therapeuticantibody, a polypeptide, a protein or other chemical, such as an iron,for example, ferumoxytol, iron dextrans, ferric glyconate, and ironsucrose. The pharmaceutical product may be in liquid form, orreconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins setforth below, including fusions, fragments, analogs, variants orderivatives thereof:

OPGL specific antibodies, peptibodies, and related proteins, and thelike (also referred to as RANKL specific antibodies, peptibodies and thelike), including fully humanized and human OPGL specific antibodies,particularly fully humanized monoclonal antibodies, including but notlimited to the antibodies described in PCT Publication No. WO 03/002713,which is incorporated herein in its entirety as to OPGL specificantibodies and antibody related proteins, particularly those having thesequences set forth therein, particularly, but not limited to, thosedenoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including theOPGL specific antibodies having either the light chain of SEQ ID NO:2 asset forth therein in FIG. 2 and/or the heavy chain of SEQ ID NO:4, asset forth therein in FIG. 4 , each of which is individually andspecifically incorporated by reference herein in its entirety fully asdisclosed in the foregoing publication;

Myostatin binding proteins, peptibodies, and related proteins, and thelike, including myostatin specific peptibodies, particularly thosedescribed in U.S. Publication No. 2004/0181033 and PCT Publication No.WO 2004/058988, which are incorporated by reference herein in theirentirety particularly in parts pertinent to myostatin specificpeptibodies, including but not limited to peptibodies of the mTN8-19family, including those of SEQ ID NOS:305-351, including TN8-19-1through TN8-19-40, TN8-19 con1 and TN8-19 con2; peptibodies of the mL2family of SEQ ID NOS:357-383; the mL15 family of SEQ ID NOS:384-409; themL17 family of SEQ ID NOS:410-438; the mL20 family of SEQ IDNOS:439-446; the mL21 family of SEQ ID NOS:447-452; the mL24 family ofSEQ ID NOS:453-454; and those of SEQ ID NOS:615-631, each of which isindividually and specifically incorporated by reference herein in theirentirety fully as disclosed in the foregoing publication;

IL-4 receptor specific antibodies, peptibodies, and related proteins,and the like, particularly those that inhibit activities mediated bybinding of IL-4 and/or IL-13 to the receptor, including those describedin PCT Publication No. WO 2005/047331 or PCT Application No.PCT/US2004/37242 and in U.S. Publication No. 2005/112694, which areincorporated herein by reference in their entirety particularly in partspertinent to IL-4 receptor specific antibodies, particularly suchantibodies as are described therein, particularly, and withoutlimitation, those designated therein: L1H1; L1H2; L1H3; L1H4; L1H5;L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5;L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1;L5H1; L6H1, each of which is individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication;

Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies,and related proteins, and the like, including but not limited to thosedescribed in U.S. Publication No. 2004/097712, which is incorporatedherein by reference in its entirety in parts pertinent to IL1-R1specific binding proteins, monoclonal antibodies in particular,especially, without limitation, those designated therein: 15CA, 26F5,27F2, 24E12, and 10H7, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe aforementioned publication;

Ang2 specific antibodies, peptibodies, and related proteins, and thelike, including but not limited to those described in PCT PublicationNo. WO 03/057134 and U.S. Publication No. 2003/0229023, each of which isincorporated herein by reference in its entirety particularly in partspertinent to Ang2 specific antibodies and peptibodies and the like,especially those of sequences described therein and including but notlimited to: L1(N); L1(N) WT; L1(N) 1K WT; 2×L1(N); 2×L1(N) WT; Con4 (N),Con4 (N) 1K WT, 2×Con4 (N) 1K; L1C; L1C 1K; 2×L1C; Con4C; Con4C 1K;2×Con4C 1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N);TN8-14 (N); Con 1 (N), also including anti-Ang 2 antibodies andformulations such as those described in PCT Publication No. WO2003/030833 which is incorporated herein by reference in its entirety asto the same, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536;Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558;Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12;AblA1; AbIF; AblK, AbIP; and AbIP, in their various permutations asdescribed therein, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

NGF specific antibodies, peptibodies, and related proteins, and the likeincluding, in particular, but not limited to those described in U.S.Publication No. 2005/0074821 and U.S. Pat. No. 6,919,426, which areincorporated herein by reference in their entirety particularly as toNGF-specific antibodies and related proteins in this regard, includingin particular, but not limited to, the NGF-specific antibodies thereindesignated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11, each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

CD22 specific antibodies, peptibodies, and related proteins, and thelike, such as those described in U.S. Pat. No. 5,789,554, which isincorporated herein by reference in its entirety as to CD22 specificantibodies and related proteins, particularly human CD22 specificantibodies, such as but not limited to humanized and fully humanantibodies, including but not limited to humanized and fully humanmonoclonal antibodies, particularly including but not limited to humanCD22 specific IgG antibodies, such as, for instance, a dimer of ahuman-mouse monoclonal hLL2 gamma-chain disulfide linked to ahuman-mouse monoclonal hLL2 kappa-chain, including, but limited to, forexample, the human CD22 specific fully humanized antibody inEpratuzumab, CAS registry number 501423-23-0;

IGF-1 receptor specific antibodies, peptibodies, and related proteins,and the like, such as those described in PCT Publication No. WO06/069202, which is incorporated herein by reference in its entirety asto IGF-1 receptor specific antibodies and related proteins, includingbut not limited to the IGF-1 specific antibodies therein designatedL1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11,L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20,L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29,L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38,L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47,L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments andderivatives thereof, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

Also among non-limiting examples of anti-IGF-1R antibodies for use inthe methods and compositions of the present disclosure are each and allof those described in:

(i) U.S. Publication No. 2006/0040358 (published Feb. 23, 2006),2005/0008642 (published Jan. 13, 2005), 2004/0228859 (published Nov. 18,2004), including but not limited to, for instance, antibody 1A (DSMZDeposit No. DSM ACC 2586), antibody 8 (DSMZ Deposit No. DSM ACC 2589),antibody 23 (DSMZ Deposit No. DSM ACC 2588) and antibody 18 as describedtherein;

(ii) PCT Publication No. WO 06/138729 (published Dec. 28, 2006) and WO05/016970 (published Feb. 24, 2005), and Lu et al. (2004), J. Biol.Chem. 279:2856-2865, including but not limited to antibodies 2F8, A12,and IMC-A12 as described therein;

(iii) PCT Publication No. WO 07/012614 (published Feb. 1, 2007), WO07/000328 (published Jan. 4, 2007), WO 06/013472 (published Feb. 9,2006), WO 05/058967 (published Jun. 30, 2005), and WO 03/059951(published Jul. 24, 2003);

(iv) U.S. Publication No. 2005/0084906 (published Apr. 21, 2005),including but not limited to antibody 7C10, chimaeric antibody C7C10,antibody h7C10, antibody 7H2M, chimaeric antibody *7C10, antibody GM607, humanized antibody 7C10 version 1, humanized antibody 7C10 version2, humanized antibody 7C10 version 3, and antibody 7H2HM, as describedtherein;

(v) U.S. Publication Nos. 2005/0249728 (published Nov. 10, 2005),2005/0186203 (published Aug. 25, 2005), 2004/0265307 (published Dec. 30,2004), and 2003/0235582 (published Dec. 25, 2003) and Maloney et al.(2003), Cancer Res. 63:5073-5083, including but not limited to antibodyEM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1,huEM164 v1.2, and huEM164 v1.3 as described therein;

(vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), U.S. Publication Nos.2005/0244408 (published Nov. 30, 2005) and 2004/0086503 (published May6, 2004), and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073,e.g., antibody CP-751,871, including but not limited to each of theantibodies produced by the hybridomas having the ATCC accession numbersPTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, andantibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, asdescribed therein;

(vii) U.S. Publication Nos. 2005/0136063 (published Jun. 23, 2005) and2004/0018191 (published Jan. 29, 2004), including but not limited toantibody 19D12 and an antibody comprising a heavy chain encoded by apolynucleotide in plasmid 15H12/19D12 HCA (y4), deposited at the ATCCunder number PTA-5214, and a light chain encoded by a polynucleotide inplasmid 15H12/19D12 LCF (K), deposited at the ATCC under numberPTA-5220, as described therein; and

(viii) U.S. Publication No. 2004/0202655 (published Oct. 14, 2004),including but not limited to antibodies PINT-6A1, PINT-7A2, PINT-7A4,PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3,PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2,PINT-12A3, PINT-12A4, and PINT-12A5, as described therein; each and allof which are herein incorporated by reference in their entireties,particularly as to the aforementioned antibodies, peptibodies, andrelated proteins and the like that target IGF-1 receptors;

B-7 related protein 1 specific antibodies, peptibodies, related proteinsand the like (“B7RP-1,” also is referred to in the literature as B7H2,ICOSL, B7h, and CD275), particularly B7RP-specific fully humanmonoclonal IgG2 antibodies, particularly fully human IgG2 monoclonalantibody that binds an epitope in the first immunoglobulin-like domainof B7RP-1, especially those that inhibit the interaction of B7RP-1 withits natural receptor, ICOS, on activated T cells in particular,especially, in all of the foregoing regards, those disclosed in U.S.Publication No. 2008/0166352 and PCT Publication No. WO 07/011941, whichare incorporated herein by reference in their entireties as to suchantibodies and related proteins, including but not limited to antibodiesdesignated therein as follow: 16H (having light chain variable and heavychain variable sequences SEQ ID NO:1 and SEQ ID NO:7 respectivelytherein); 5D (having light chain variable and heavy chain variablesequences SEQ ID NO:2 and SEQ ID NO:9 respectively therein); 2H (havinglight chain variable and heavy chain variable sequences SEQ ID NO:3 andSEQ ID NO:10 respectively therein); 43H (having light chain variable andheavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14 respectivelytherein); 41H (having light chain variable and heavy chain variablesequences SEQ ID NO:5 and SEQ ID NO:13 respectively therein); and 15H(having light chain variable and heavy chain variable sequences SEQ IDNO:4 and SEQ ID NO:12 respectively therein), each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

IL-15 specific antibodies, peptibodies, and related proteins, and thelike, such as, in particular, humanized monoclonal antibodies,particularly antibodies such as those disclosed in U.S. Publication Nos.2003/0138421; 2003/023586; and 2004/0071702; and U.S. Pat. No.7,153,507, each of which is incorporated herein by reference in itsentirety as to IL-15 specific antibodies and related proteins, includingpeptibodies, including particularly, for instance, but not limited to,HuMax IL-15 antibodies and related proteins, such as, for instance,146B7;

IFN gamma specific antibodies, peptibodies, and related proteins and thelike, especially human IFN gamma specific antibodies, particularly fullyhuman anti-IFN gamma antibodies, such as, for instance, those describedin U.S. Publication No. 2005/0004353, which is incorporated herein byreference in its entirety as to IFN gamma specific antibodies,particularly, for example, the antibodies therein designated 1118;1118*; 1119; 1121; and 1121*. The entire sequences of the heavy andlight chains of each of these antibodies, as well as the sequences oftheir heavy and light chain variable regions and complementaritydetermining regions, are each individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. Inaddition, description of the properties of these antibodies provided inthe foregoing publication is also incorporated by reference herein inits entirety. Specific antibodies include those having the heavy chainof SEQ ID NO:17 and the light chain of SEQ ID NO:18; those having theheavy chain variable region of SEQ ID NO:6 and the light chain variableregion of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 andthe light chain of SEQ ID NO:20; those having the heavy chain variableregion of SEQ ID NO:10 and the light chain variable region of SEQ IDNO:12; those having the heavy chain of SEQ ID NO:32 and the light chainof SEQ ID NO:20; those having the heavy chain variable region of SEQ IDNO:30 and the light chain variable region of SEQ ID NO:12; those havingthe heavy chain sequence of SEQ ID NO:21 and the light chain sequence ofSEQ ID NO:22; those having the heavy chain variable region of SEQ IDNO:14 and the light chain variable region of SEQ ID NO:16; those havingthe heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; andthose having the heavy chain variable region of SEQ ID NO:14 and thelight chain variable region of SEQ ID NO:31, as disclosed in theforegoing publication. A specific antibody contemplated is antibody 1119as disclosed in the foregoing U.S. publication and having a completeheavy chain of SEQ ID NO:17 as disclosed therein and having a completelight chain of SEQ ID NO:18 as disclosed therein;

TALL-1 specific antibodies, peptibodies, and the related proteins, andthe like, and other TALL specific binding proteins, such as thosedescribed in U.S. Publication Nos. 2003/0195156 and 2006/0135431, eachof which is incorporated herein by reference in its entirety as toTALL-1 binding proteins, particularly the molecules of Tables 4 and 5B,each of which is individually and specifically incorporated by referenceherein in its entirety fully as disclosed in the foregoing publications;

Parathyroid hormone (“PTH”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,756,480, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind PTH;

Thrombopoietin receptor (“TPO-R”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,835,809, which is herein incorporated by reference in its entirety,particularly in parts pertinent to proteins that bind TPO-R;

Hepatocyte growth factor (“HGF”) specific antibodies, peptibodies, andrelated proteins, and the like, including those that target theHGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human monoclonalantibodies that neutralize hepatocyte growth factor/scatter (HGF/SF)described in U.S. Publication No. 2005/0118643 and PCT Publication No.WO 2005/017107, huL2G7 described in U.S. Pat. No. 7,220,410 and OA-5d5described in U.S. Pat. Nos. 5,686,292 and 6,468,529 and in PCTPublication No. WO 96/38557, each of which is incorporated herein byreference in its entirety, particularly in parts pertinent to proteinsthat bind HGF;

TRAIL-R2 specific antibodies, peptibodies, related proteins and thelike, such as those described in U.S. Pat. No. 7,521,048, which isherein incorporated by reference in its entirety, particularly in partspertinent to proteins that bind TRAIL-R2;

Activin A specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. PublicationNo. 2009/0234106, which is herein incorporated by reference in itsentirety, particularly in parts pertinent to proteins that bind ActivinA;

TGF-beta specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. Pat. No.6,803,453 and U.S. Publication No. 2007/0110747, each of which is hereinincorporated by reference in its entirety, particularly in partspertinent to proteins that bind TGF-beta;

Amyloid-beta protein specific antibodies, peptibodies, related proteins,and the like, including but not limited to those described in PCTPublication No. WO 2006/081171, which is herein incorporated byreference in its entirety, particularly in parts pertinent to proteinsthat bind amyloid-beta proteins. One antibody contemplated is anantibody having a heavy chain variable region comprising SEQ ID NO:8 anda light chain variable region having SEQ ID NO:6 as disclosed in theforegoing publication;

c-Kit specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2007/0253951, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind c-Kit and/or otherstem cell factor receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2006/0002929, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind OX40L and/or otherligands of the OX40 receptor; and

Other exemplary proteins, including Activase® (alteplase, tPA); Aranesp®(darbepoetin alfa); Epogen® (epoetin alfa, or erythropoietin); GLP-1,Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonalantibody); Betaseron® (interferon-beta); Campath® (alemtuzumab,anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade®(bortezomib); MLN0002 (anti-α4β7 mAb); MLN1202 (anti-CCR2 chemokinereceptor mAb); Enbrel® (etanercept, TNF-receptor/Fc fusion protein, TNFblocker); Eprex® (epoetin alfa); Erbitux® (cetuximab,anti-EGFR/HER1/c-ErbB-1); Genotropin® (somatropin, Human GrowthHormone); Herceptin® (trastuzumab, anti-HER2/neu (erbB2) receptor mAb);Humatrope® (somatropin, Human Growth Hormone); Humira® (adalimumab);insulin in solution; Infergen® (interferon alfacon-1); Natrecor®(nesiritide; recombinant human B-type natriuretic peptide (hBNP);Kineret® (anakinra); Leukine® (sargamostim, rhuGM-CSF); LymphoCide®(epratuzumab, anti-CD22 mAb); Benlysta™ (lymphostat B, belimumab,anti-BlyS mAb); Metalyse® (tenecteplase, t-PA analog); Mircera® (methoxypolyethylene glycol-epoetin beta); Mylotarg® (gemtuzumab ozogamicin);Raptiva® (efalizumab); Cimzia® (certolizumab pegol, CDP 870); Soliris™(eculizumab); pexelizumab (anti-C5 complement); Numax® (MEDI-524);Lucentis® (ranibizumab); Panorex® (17-1A, edrecolomab); Trabio®(lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4);Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (visilizumab); cantuzumabmertansine (huC242-DM1); NeoRecormon® (epoetin beta); Neumega®(oprelvekin, human interleukin-11); Neulasta® (pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF); Neupogen® (filgrastim, G-CSF,hu-MetG-CSF); Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonalantibody); Procrit® (epoetin alfa); Remicade® (infliximab, anti-TNFαmonoclonal antibody); Reopro® (abciximab, anti-GP IIb/IIia receptormonoclonal antibody); Actemra® (anti-IL6 Receptor mAb); Avastin®(bevacizumab), HuMax-CD4 (zanolimumab); Rituxan® (rituximab, anti-CD20mAb); Tarceva® (erlotinib); Roferon-A®-(interferon alfa-2a); Simulect®(basiliximab); Prexige® (lumiracoxib); Synagis® (palivizumab); 146B7-CHO(anti-IL15 antibody, see U.S. Pat. No. 7,153,507); Tysabri®(natalizumab, anti-α4integrin mAb); Valortim® (MDX-1303, anti-B.anthracis protective antigen mAb); ABthrax™; Vectibix® (panitumumab);Xolair® (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (the Fc portionof human IgG1 and the extracellular domains of both IL-1 receptorcomponents (the Type I receptor and receptor accessory protein)); VEGFtrap (Ig domains of VEGFR1 fused to IgG1 Fc); Zenapax® (daclizumab);Zenapax® (daclizumab, anti-IL-2Ra mAb); Zevalin® (ibritumomab tiuxetan);Zetia® (ezetimibe); Orencia® (atacicept, TACI-Ig); anti-CD80 monoclonalantibody (galiximab); anti-CD23 mAb (lumiliximab); BR2-Fc (huBR3/huFcfusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNFαmAb); HGS-ETR1 (mapatumumab; human anti-TRAIL Receptor-1 mAb);HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (zalutumumab);M200 (volociximab, anti-α5β1 integrin mAb); MDX-010 (ipilimumab,anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-C. difficileToxin A and Toxin B C mAbs MDX-066 (CDA-1) and MDX-1388); anti-CD22dsFv-PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC);anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333(anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb; anti-CriptomAb; anti-CTGF Idiopathic Pulmonary Fibrosis Phase I Fibrogen (FG-3019);anti-CTLA4 mAb; anti-eotaxinl mAb (CAT-213); anti-FGF8 mAb;anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb(MYO-029); anti-GM-CSF Receptor mAb (CAM-3001); anti-HepC mAb (HuMaxHepC); anti-IFNα mAb (MEDI-545, MDX-1103); anti-IGF1R mAb; anti-IGF-1RmAb (HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12/1L23 mAb (CNTO1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC); anti-IL5Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO 95); anti-IP10Ulcerative Colitis mAb (MDX-1100); anti-LLY antibody; BMS-66513;anti-Mannose Receptor/hCGβ mAb (MDX-1307); anti-mesothelin dsFv-PE38conjugate (CAT-5001); anti-PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFRαantibody (IMC-3G3); anti-TGFβ mAb (GC-1008); anti-TRAIL Receptor-2 humanmAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb; anti-ZP3 mAb(HuMax-ZP3); NVS Antibody #1; and NVS Antibody #2.

Also included can be a sclerostin antibody, such as but not limited toromosozumab, blosozumab, or BPS 804 (Novartis). Further included can betherapeutics such as rilotumumab, bixalomer, trebananib, ganitumab,conatumumab, motesanib diphosphate, brodalumab, vidupiprant,panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA. Additionally,included in the device can be a monoclonal antibody (IgG) that bindshuman Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Such PCSK9specific antibodies include, but are not limited to, Repatha®(evolocumab) and Praluent® (alirocumab), as well as molecules, variants,analogs or derivatives thereof as disclosed in the following patents orpatent applications, each of which is herein incorporated by referencein its entirety for all purposes: U.S. Pat. Nos. 8,030,547, 8,563,698,8,829,165, 8,859,741, 8,871,913, 8,871,914, 8,883,983, 8,889,834,8,981,064, 9,056,915, 8,168,762, 9,045,547, 8,030,457, 8,030,457,8,829,165, 8,981,064, 8,030,457, U.S. Publication No. 2013/0064825, U.S.Patent Application Publication No. 2012/0093818, U.S. Patent ApplicationPublication No. 2013/0079502, U.S. Patent Application Publication No.2014/0357850, U.S. Patent Application Publication No. 2011/0027287, U.S.Patent Application Publication No. 2014/0357851, U.S. Patent ApplicationPublication No. 2014/0357854, U.S. Patent Application Publication No.2015/0031870, U.S. Patent Application Publication No. 2013/0085265, U.S.Patent Application Publication No. 2013/0079501, U.S. Patent ApplicationPublication No. 2012/0213797, U.S. Patent Application Publication No.2012/0251544, U.S. Patent Application Publication No. 2013/0072665, U.S.Patent Application Publication No. 2013/0058944, U.S. Patent ApplicationPublication No. 2013/0052201, U.S. Patent Application Publication No.2012/0027765, U.S. Patent Application Publication No. 2015/0087819, U.S.Patent Application Publication No. 2011/0117011, U.S. Patent ApplicationPublication No. 2015/0004174, U.S. Provisional Patent Application No.60/957,668, U.S. Provisional Patent Application No. 61/008,965, U.S.Provisional Patent Application No. 61/010,630, U.S. Provisional PatentApplication No. 61/086,133, U.S. Provisional Patent Application No.61/125,304, U.S. Provisional Patent Application No. 61/798,970, U.S.Provisional Patent Application No. 61/841,039, U.S. Provisional PatentApplication No. 62/002,623, U.S. Provisional Patent Application No.62/024,399, U.S. Provisional Patent Application No. 62/019,729, U.S.Provisional Patent Application No. 62/067,637, U.S. patent applicationSer. No. 14/777,371, International Patent Application No.PCT/US2013/048714, International Patent Application No.PCT/US2015/040211, International Patent Application No.PCT/US2015/056972, International Patent Application Publication No.WO/2008/057457, International Patent Application Publication No.WO/2008/057458, International Patent Application Publication No.WO/2008/057459, International Patent Application Publication No.WO/2008/063382, International Patent Application Publication No.WO/2008/133647, International Patent Application Publication No.WO/2009/100297, International Patent Application Publication No.WO/2009/100318, International Patent Application Publication No.WO/2011/037791, International Patent Application Publication No.WO/2011/053759, International Patent Application Publication No.WO/2011/053783, International Patent Application Publication No.WO/2008/125623, International Patent Application Publication No.WO/2011/072263, International Patent Application Publication No.WO/2009/055783, International Patent Application Publication No.WO/2012/0544438, International Patent Application Publication No.WO/2010/029513, International Patent Application Publication No.WO/2011/111007, International Patent Application Publication No.WO/2010/077854, International Patent Application Publication No.WO/2012/088313, International Patent Application Publication No.WO/2012/101251, International Patent Application Publication No.WO/2012/101252, International Patent Application Publication No.WO/2012/101253, International Patent Application Publication No.WO/2012/109530, and International Patent Application Publication No.WO/2001/031007, International Patent Application Publication No.WO/2009/026558, International Patent Application Publication No.WO/2009/131740, International Patent Application Publication No.WO/2013/166448, and International Patent Application Publication No.WO/2014/150983.

Also included can be talimogene laherparepvec or another oncolytic HSVfor the treatment of melanoma or other cancers. Examples of oncolyticHSV include, but are not limited to talimogene laherparepvec (U.S. Pat.Nos. 7,223,593 and 7,537,924); OncoVEXGALV/CD (U.S. Pat. No. 7,981,669);OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143);G207, 1716; NV1020; NV12023; NV1034 and NV1042 (Vargehes et al. (2002),Cancer Gene Ther., 9(12):967-978).

Also included are TIMPs. TIMPs are endogenous tissue inhibitors ofmetalloproteinases (TIMPs) and are important in many natural processes.TIMP-3 is expressed by various cells or and is present in theextracellular matrix; it inhibits all the major cartilage-degradingmetalloproteases, and may play a role in role in many degradativediseases of connective tissue, including rheumatoid arthritis andosteoarthritis, as well as in cancer and cardiovascular conditions. Theamino acid sequence of TIMP-3, and the nucleic acid sequence of a DNAthat encodes TIMP-3, are disclosed in U.S. Pat. No. 6,562,596, issuedMay 13, 2003, the disclosure of which is incorporated by referenceherein. Description of TIMP mutations can be found in U.S. PublicationNo. 2014/0274874 and PCT Publication No. WO 2014/152012.

Also included are antagonistic antibodies for human calcitoningene-related peptide (CGRP) receptor and bispecific antibody moleculethat target the CGRP receptor and other headache targets. Furtherinformation concerning these molecules can be found in PCT ApplicationNo. WO 2010/075238.

Additionally, a bispecific T cell engager antibody (BiTe), e.g.Blinotumomab can be used in the device. Alternatively, included can bean APJ large molecule agonist e.g., apelin or analogues thereof in thedevice. Information relating to such molecules can be found in PCTPublication No. WO 2014/099984.

In certain embodiments, the drug comprises a therapeutically effectiveamount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptorantibody. Examples of anti-TSLP antibodies that may be used in suchembodiments include, but are not limited to, those described in U.S.Pat. Nos. 7,982,016, and 8,232,372, and U.S. Publication No.2009/0186022. Examples of anti-TSLP receptor antibodies include, but arenot limited to, those described in U.S. Pat. No. 8,101,182. Inparticularly preferred embodiments, the drug comprises a therapeuticallyeffective amount of the anti-TSLP antibody designated as A5 within U.S.Pat. No. 7,982,016.

While the present disclosure has been described in connection withvarious embodiments, it will be understood that the present disclosureis capable of further modifications. The present disclosure is intendedto cover any variations, uses, or adaptations of the disclosed subjectmatter following, in general, the principles of the present disclosure,and including such departures from the present disclosure as, within theknown and customary practice within the art to which the presentdisclosure pertains.

It is noted that the construction and arrangement of the drug deliverydevice and its various components and assemblies as shown in the variousexemplary embodiments is illustrative only. Although only a fewembodiments of the subject matter at issue have been described in detailin the present disclosure, those skilled in the art who review thepresent disclosure will readily appreciate that many modifications arepossible (e.g., variations in sizes, dimensions, structures, shapes andproportions of the various elements, values of parameters, mountingarrangements, use of materials, colors, orientations, etc.) withoutmaterially departing from the novel teachings and advantages of thesubject matter disclosed herein. For example, elements shown asintegrally formed may be constructed of multiple parts or elements, andvice versa. Also, the position of elements may be reversed or otherwisevaried, and the nature or number of discrete elements or positions maybe altered or varied. Accordingly, all such modifications are intendedto be included within the scope of the present disclosure as defined inthe appended claims. Furthermore, the order or sequence of any processor method steps may be varied or re-sequenced according to alternativeembodiments. Other substitutions, modifications, changes and omissionsmay be made in the design, operating conditions and arrangement of thevarious exemplary embodiments without departing from the scope of thepresent disclosure.

What is claimed is:
 1. A drug delivery device comprising: a housing; acontainer disposed in the housing and having an interior volume and anend surface, an opening being formed in the end surface andcommunicating with the interior volume; a drug disposed in the interiorvolume of the container; a septum including a proximal end and a distalend, the proximal end being inserted through the opening into theinterior volume of the container, the distal end including a flangedisposed outwardly of the proximal end and a distally facing endsurface; a needle disposed through or configured to be disposed throughat least a portion of the septum; a diffusive pathway at the distal endof the septum and contacting the end surface of the container, thediffusive pathway being made of a first material that is permeable to agaseous sterilizing agent; and wherein at least the distally facing endsurface of the at least a portion of the septum is made of a secondmaterial that is less permeable to the gaseous sterilizing agent thanthe first material.
 2. The drug delivery device of claim 1, wherein theflange includes an end portion defining the diffusive pathway, the endportion having a proximally facing surface sealingly engaging the endsurface of the container to inhibit the ingress of contaminants.
 3. Thedrug delivery device of claim 2, the proximal end of the septum beingmade of the second material.
 4. The drug delivery device of claim 2, thedistal end of the septum being made entirely from the second materialexcept for the end portion of the flange.
 5. The drug delivery device ofclaim 2, the end portion of the flange having an outer peripheralsurface which is exposed to the gaseous sterilizing agent during asterilization procedure.
 6. The drug delivery device of claim 2, alength of the end portion of the flange being less than an overalllength of the flange, and a width of the end portion of the flange beingequal to an overall width of the flange.
 7. The drug delivery device ofclaim 1, a portion of the distal end of the septum arranged distallyrelative to the flange being made of the second material.
 8. The drugdelivery device of claim 7, the proximal end of the septum being made ofthe first material.
 9. The drug delivery device of claim 1, comprising aring-shaped sealing member constructed of the first material anddefining the diffusive pathway, the ring-shaped sealing member separatefrom the septum and positioned between the flange and the end surface ofthe container.
 10. A container assembly comprising: a container havingan interior volume and an end surface, an opening being formed in theend surface, communicating with the interior volume, and being centeredgenerally about a longitudinal axis of the container; a septum includinga proximal end and a distal end, the proximal end being insertablethrough the opening into the interior volume of the container, thedistal end including a flange disposed outwardly of the proximal end anda distally facing end surface, the longitudinal axis of the containerextending through at least a portion of the septum; a diffusive pathwayat the distal end of the septum and contacting the end surface of thecontainer, the diffusive pathway being made of a first material that ispermeable to a gaseous sterilizing agent; and wherein at least thedistally facing end surface of the at least a portion of the septum ismade of a second material that is less permeable to the gaseoussterilizing agent than the first material.
 11. The container assembly ofclaim 10, the proximal end of the septum being made of the secondmaterial.
 12. The container assembly of claim 11, wherein the flange ofthe septum includes an end portion defining the diffusive pathway, theend portion having a proximally facing surface sealingly engaging theend surface of the container to inhibit the ingress of contaminants, andthe distal end of the septum being made entirely from the secondmaterial except for the end portion of the flange.
 13. The containerassembly of claim 10, the proximal end of the septum being made of thefirst material, and a portion of the distal end of the septum arrangeddistally relative to the flange being made of the second material. 14.The container assembly of claim 10, comprising a ring-shaped sealingmember constructed of the first material and defining the diffusivepathway, the ring-shaped sealing member separate from the septum andpositioned between the flange and the end surface of the container. 15.A drug delivery device comprising: a housing; a container disposed inthe housing and having an interior volume and an end surface, an openingbeing formed in the end surface and communicating with the interiorvolume; a drug disposed in the interior volume of the container; aseptum including a proximal end and a distal end, the proximal end beinginserted through the opening into the interior volume of the container,the distal end including a flange disposed outwardly of the proximalend; a diffusive pathway at the distal end of the septum and contactingthe end surface of the container, the diffusive pathway being made of afirst material that is permeable to a gaseous sterilizing agent; whereinthe flange includes an end portion defining the diffusive pathway, theend portion having a proximally facing surface sealingly engaging theend surface of the container to inhibit the ingress of contaminants; andthe distal end of the septum being made entirely from a second materialexcept for the end portion of the flange, the second material being lesspermeable than the first material.
 16. A drug delivery devicecomprising: a housing; a container disposed in the housing and having aninterior volume and an end surface, an opening being formed in the endsurface and communicating with the interior volume; a drug disposed inthe interior volume of the container; a septum including a proximal endand a distal end, the proximal end being inserted through the openinginto the interior volume of the container, the distal end including aflange disposed outwardly of the proximal end; a diffusive pathway atthe distal end of the septum and contacting the end surface of thecontainer, the diffusive pathway being made of a first material that ispermeable to a gaseous sterilizing agent; and a portion of the distalend of the septum arranged distally relative to the flange being made ofa second material, the second material being less permeable than thefirst material.
 17. A drug delivery device comprising: a housing; acontainer disposed in the housing and having an interior volume and anend surface, an opening being formed in the end surface andcommunicating with the interior volume; a drug disposed in the interiorvolume of the container; a septum including a proximal end and a distalend, the proximal end being inserted through the opening into theinterior volume of the container, the distal end including a flangedisposed outwardly of the proximal end; a diffusive pathway at thedistal end of the septum and contacting the end surface of thecontainer, the diffusive pathway being made of a first material that ispermeable to a gaseous sterilizing agent; and comprising a ring-shapedsealing member constructed of the first material and defining thediffusive pathway, the ring-shaped sealing member separate from theseptum and positioned between the flange and the end surface of thecontainer.
 18. A container assembly comprising: a container having aninterior volume and an end surface, an opening being formed in the endsurface and communicating with the interior volume; a septum including aproximal end and a distal end, the proximal end being insertable throughthe opening into the interior volume of the container, the distal endincluding a flange disposed outwardly of the proximal end; a diffusivepathway at the distal end of the septum and contacting the end surfaceof the container, the diffusive pathway being made of a first materialthat is permeable to a gaseous sterilizing agent; the proximal end ofthe septum being made of a second material, the second material beingless permeable than the first material; and wherein the flange of theseptum includes an end portion defining the diffusive pathway, the endportion having a proximally facing surface sealingly engaging the endsurface of the container to inhibit the ingress of contaminants, and thedistal end of the septum being made entirely from the second materialexcept for the end portion of the flange.
 19. A container assemblycomprising: a container having an interior volume and an end surface, anopening being formed in the end surface and communicating with theinterior volume; a septum including a proximal end and a distal end, theproximal end being insertable through the opening into the interiorvolume of the container, the distal end including a flange disposedoutwardly of the proximal end; a diffusive pathway at the distal end ofthe septum and contacting the end surface of the container, thediffusive pathway being made of a first material that is permeable to agaseous sterilizing agent; and the proximal end of the septum being madeof the first material, and a portion of the distal end of the septumarranged distally relative to the flange being made of a secondmaterial, wherein the second material is less permeable than the firstmaterial.
 20. A container assembly comprising: a container having aninterior volume and an end surface, an opening being formed in the endsurface and communicating with the interior volume; a septum including aproximal end and a distal end, the proximal end being insertable throughthe opening into the interior volume of the container, the distal endincluding a flange disposed outwardly of the proximal end; a diffusivepathway at the distal end of the septum and contacting the end surfaceof the container, the diffusive pathway being made of a first materialthat is permeable to a gaseous sterilizing agent; and a ring-shapedsealing member constructed of the first material and defining thediffusive pathway, the ring-shaped sealing member separate from theseptum and positioned between the flange and the end surface of thecontainer.